The overall goal of this long-standing program project (in its 16th year) is to achieve a total control of nephrolithiasis, by pursuing pathophysiological elucidation using metabolic and molecular approaches, and by formulating innovative treatments that are safe and effective. In Component I, pathogenetic role of vitamin D for increased Ca absorption in absorptive hypercalciuria will be sought by examining monocytes, skin fibroblasts and osteoblasts for abnormality in vitamin D receptor gene and function. Moreover, response to a new drug (UroPhos-K or slow release neutral potassium phosphate) will be elucidated in order to determine whether this treatment would provide a complete or partial correction of absorptive hypercalciuria. In Component II, Na/citrate co-transporter gene will be cloned in order to determine molecular basis for renal hypocitraturia, a condition characterized by defective citrate excretion in the absence of RTA or bowel disease. Component III will be concerned with the laboratory and clinical aspects of extracorporeal shock wave lithotripsy (ESWL). Etiological role of free radicals in renal tissue damage post-lithotripsy will be examined, and the work on computer modelling and physics of lithotripsy will be continued. Clinically, a randomized trial with potassium-magnesium citrate (K-Mag) will be conducted during peri-ESWL period, in order to determine if this treatment would avert residual calculi. Component IV will seek new, improved treatments for nephrolithiasis. They include UroPhos-K for absorptive hypercalciuria, K-Mag in hypocitraturia, bucillamine (a dithiol compound) in cystinuria, and aminobutylidine diphosphonate in immobilization. Careful randomized metabolic studies, as well as long-term trials, are plan d.